title: Sodium overload due to a persistent current that attenuates the arrhythmogenic potential of a novel LQT3 mutation.
abstract: Long QT syndrome (LQTS) is a congenital abnormality of cardiac repolarization that manifests as a prolonged QT interval on 12-lead electrocardiograms (ECGs). The syndrome may lead to syncope and sudden death from ventricular tachyarrhythmias known as torsades de pointes. An increased persistent Na(+) current is known to cause a Ca(2+) overload in case of ischemia for example. Such increased Na(+) persistent current is also usually associated to the LQT3 syndrome. The purpose of this study was to investigate the pathological consequences of a novel mutation in a family affected by LQTS. The impact of biophysical defects on cellular homeostasis are also investigated. Genomic DNA was extracted from blood samples, and a combination of PCR and DNA sequencing of several LQTS-linked genes was used to identify mutations. The mutation was reproduced in vitro and was characterized using the patch clamp technique and in silico quantitative analysis. A novel mutation (Q1476R) was identified on the SCN5A gene encoding the cardiac Na(+) channel. Cells expressing the Q1476R mutation exhibited biophysical alterations, including a shift of SS inactivation and a significant increase in the persistent Na(+) current. The in silico analysis confirmed the arrhythmogenic character of the Q1476R mutation. It further revealed that the increase in persistent Na(+) current causes a frequency-dependent Na(+) overload in cardiomyocytes co-expressing WT and mutant Nav1.5 channels that, in turn, exerts a moderating effect on the lengthening of the action potential (AP) duration caused by the mutation. The Q1476R mutation in SCN5A results in a three-fold increase in the window current and a persistent inward Na(+) current. These biophysical defects may expose the carrier of the mutation to arrhythmias that occur preferentially in the patient at rest or during tachycardia. However, the Na(+) overload counterbalances the gain-of-function of the mutation and is beneficial in that it prevents severe arrhythmias at intermediate heart rates.
authors.affiliation: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec City QC, Canada.
authors.forename: Adrien
authors.initials: A
authors.lastname: Moreau
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krahn
authors.forename: Pascal
authors.initials: P
authors.lastname: Gosselin-Badaroudine
authors.forename: George J
authors.initials: GJ
authors.lastname: Klein
authors.forename: Georges
authors.initials: G
authors.lastname: Christé
authors.forename: Yohann
authors.initials: Y
authors.lastname: Vincent
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boutjdir
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
keywords: LQT3; Nav1.5; cardiac arrhythmia; electrophysiology; heart; long QT syndrome; sodium overload